Human exposure to environmental pollutants has been proposes as a risk factor for endocrine disruption and the development of cancers of the breast and reproductive tract. Environmental pollutants are thought to exert effects on the endocrine system in part by influences the activities of nuclear hormone receptors that regulate diver aspects of growth, development and homeostasis. Some of the most common environmental pollutants found at Superfund Sites, including polychlorinated biphenyls (PCBs) and phthalates, can bind to members of the nuclear receptor superfamily and regulate their activities. These chemicals therefore have the potential for disrupting normal programs of endocrine regulation, resulting in disease. The major goals of this multi disciplinary research program are to use recombinant DNA approaches to assess the impact of exposure to Superfund chemicals on cellular and molecular events that affect the regulation of gene expression. In this project, we propose to take advantage of recent developments that affect the regulation of gene expression. In this project, we propose to take advantage of recent developments in the molecular biology of nuclear receptors to develop novel methods to assess effects of environmental pollutants on specific endocrine signaling pathways in transgenic mice. These methodologies, which can be tailored to allow evaluation of effects of environmental pollutants on human receptors in an in vivo setting, are potentially applicable to all members of the nuclear receptor super family. These methods will initially be developed to assess effects of Superfund site chemicals on estrogen and peroxisome proliferator activated receptor function. Estrogen receptors represent one of the most intensively studied targets of endocrine disruptors, allowing validation of these new methodologies by comparison to existing assay systems. The peroxisome proliferator activated receptors are much less well understood, but represent important emerging targets of endocrine disrupting compounds. The specific aims of this proposal are to: 1) Develop transgenic reporter systems that allow quantitative assessment of the transcriptional activities of estrogen and peroxisome endogenous hormones and identify physiologic target genes; and 3) Assess effects of endocrine disrupters found at Superfund Sites on the activities of estrogen and peroxisome- proliferator-activated receptors in vivo and their effects on the expression of downstream target genes.